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BX471
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
BX471图片
CAS NO:217645-70-0
规格:≥98%
包装与价格:
包装价格(元)
1mg电议
2mg电议
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 434.89
Formula C21H24ClFN4O3
CAS No. 217645-70-0 (free base)
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: ≥ 51 mg/mL
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)C[C@H]1N(C(COC2=CC=C(Cl)C=C2NC(N)=O)=O)CCN(CC3=CC=C(F)C=C3)C1
Synonyms

ZK811752; ZK 811752; ZK-811752; BX471; BX 471; BX-471

Chemical Name: (R)-1-(5-chloro-2-(2-(4-(4-fluorobenzyl)-2-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)urea

实验参考方法
In Vitro

In vitro activity: BX471 (also known as ZK-811752) is a novel, oral and non-peptide antagonist of CCR1 (CC chemokine receptor-1) with Ki of 1 nM for human CCR1, and it may be useful in the treatment of chronic inflammatory diseases. BX471 exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4. CCR1 is a prime therapeutic target for treating autoimmune diseases. BX 471 demonstrates a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis.


Kinase Assay: BX471 (also known as ZK-811752) is a novel, oral and non-peptide antagonist of CCR1 (CC chemokine receptor-1) with Ki of 1 nM for human CCR1, and it may be useful in the treatment of chronic inflammatory diseases. BX471 exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4. CCR1 is a prime therapeutic target for treating autoimmune diseases.


Cell Assay: BX471 (0.1-10 μM) shows a dose-dependent inhibition of RANTES-mediated and shear-resistant adhesion on IL-1β-activated microvascular endothelium in shear flow in isolated blood monocytes. BX471 also inhibits the RANTES-mediated adhesion of T lymphocytes to activated endothelium.BX471 is also able to displace 125I-MIP-1α/CCL3 binding to mouse CCR1 in a concentration-dependent manner with a Ki of 215±46 nM. Increasing concentrations of BX471 inhibits the Ca2+ transients induced by MIP-1α/CCL3 in both human and mouse CCR1 with IC50 of 5.8±1 nM and 198±7 nM, respectively.BX 471 is a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca2+mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrats a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors.

In VivoBX471 (20 mg/kg, s.c.) reaches peak plasma levels of 9 μM by around 30 minutes, and this rapidly declines to approximately 0.4 μM after 2 hours. From 4 to 8 hours the drug plasma levels drops to 0.1 μM or lower. Mice treated with 20 mg/kg of BX471 for 10 days shows a reduction of interstitial CD45 positive leukocytes of approximately 55%. BX471 has a borderline significant effect on the number of CCR5-positive CD8 cells in the peripheral blood. BX471 reduces the amount of FSP1-positive cells by 65% in UUO kidneys as compared with vehicle control.Pretreatment witih BX471 reduces macrophage and neutrophil accumulation in kidney after ischemia-reperfusion injury.BX 471 (4 mg/kg, p.o. or i.v.) is orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis.
Animal model Mice (PD model) and dogs (PK model)
Formulation & Dosage Mice: 20 mg/kg, s.c.; Dog: 4 mg/kg, i.v. or p.o.
References J Biol Chem. 2001 Feb 9;276(6):4199-204. Epub 2000 Oct 27; J Biol Chem. 2000 Jun 23;275(25):19000-8; J Clin Invest. 2002 Jan;109(2):251-9.J Immunol. 2008 Dec 15;181(12):8670-6.